期刊
MOLECULAR BIOLOGY OF THE CELL
卷 20, 期 6, 页码 1715-1727出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E08-05-0451
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资金
- Spanish Ministry of Education and Sciences (SMES) [SAF2005-00130, SAF2008-0462, SAF2006-01789]
- Junta de Extremadura [2PR04A060]
- Red Temdouble daggertica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/1016, RD06/0020/0001]
- Fondo de Investigaciones Sanitarias (FIS)
- Carlos III Institute
- Spanish Ministry of Health
- US National Cancer Institute/NIH [5R01-CA73735-11]
- Castilla-Leon Autonomous Government [SA053A05]
- European Union FEDER program.
The dioxin receptor (AhR) modulates cell plasticity and migration, although the signaling involved remains unknown. Here, we report a mechanism that integrates AhR into these cytoskeleton-related functions. Immortalized and mouse embryonic fibroblasts lacking AhR (AhR-/-) had increased cell area due to spread cytoplasms that reverted to wild-type morphology upon AhR re-expression. The AhR-null phenotype included increased F-actin stress fibers, depolarized focal adhesions, and enhanced spreading and adhesion. The cytoskeleton alterations of AhR-/- cells were due to down-regulation of constitutive Vav3 expression, a guanosine diphosphate/guanosine triphosphate exchange factor for Rho/Rac GTPases and a novel transcriptional target of AhR. AhR was recruited to the vav3 promoter and maintained constitutive mRNA expression in a ligand-independent manner. Consistently, AhR-/- fibroblasts had reduced Rac1 activity and increased activation of the RhoA/Rho kinase (Rock) pathway. Pharmacological inhibition of Rac1 shifted AhR+/+ fibroblasts to the null phenotype, whereas Rock inhibition changed AhR-null cells to the AhR+/+ morphology. Knockdown of vav3 transcripts by small interfering RNA induced cytoskeleton defects and changes in adhesion and spreading mimicking those of AhR-null cells. Moreover, vav3-/- MEFs, as AhR-/- mouse embryonic fibroblasts, had increased cell area and enhanced stress fibers. By modulating Vav3-dependent signaling, AhR could regulate cell shape, adhesion, and migration under physiological conditions and, perhaps, in certain pathological states.
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